Evaluation of marketed drugs for rapid development as anti-cryptosporidal agents

评价上市药物作为抗隐孢子虫药物的快速开发

• 批准号: 8285540
• 负责人: GUAN ZHU
• 金额: $ 21.98万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8285540
• 关键词: 2,4-thiazolidinedione; Acquired Immunodeficiency Syndrome; Acute; Acyl Coenzyme A; Animals; Anti-HIV Agents; Ants; Biological Assay; Categories; Cessation of life; Chemicals; Chlorine; Chronic; Cities; Clinical Trials; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Data; Development; Diarrhea; Disease Outbreaks; Drug Design; Evaluation; FDA approved; Future; Growth; Human; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Infection; Life; Ligase; Marketing; Modeling; Morbidity - disease rate; Oocysts; Parasites; Patients; Pharmaceutical Preparations; Resistance; Screening procedure; Stress; Structure-Activity Relationship; Thiazolidinediones; United States; United States National Institutes of Health; Water; Water Supply; Wisconsin; base; biodefense; drug development; drug discovery; drug market; foodborne pathogen; gastrointestinal epithelium; improved; in vitro activity; in vivo; inhibitor/antagonist; mortality; mouse model; nitazoxanide; novel; pathogen; programs; research study

DESCRIPTION (provided by applicant): Cryptosporidium parvum is an AIDS-OI pathogen and Category B agent that can cause severe watery diarrhea in humans and animals. This parasite can cause prolonged, life threatening infection in immunocompromised individuals, and is responsible for a substantial degree of morbidity and mortality in AIDS patients. Also because the infectious oocysts are highly resistant to chemical stresses, C. parvum is a significant water- and food-borne pathogen and one of the category B agent in the NIH biodefense program. Currently, no drug is FDA-approved to treat cryptosporidiosis in immunocompromised patients, although a single drug (nitazoxanide) is approved for use in immunocompetent patients in the United States. Therefore, there is an urgent need to develop new anti-Cryptosporidium drugs, particularly new drugs for AIDS patients. Encouraged by the recent development in "repurposing of existing drugs" for potential new indications, as well as based on our unexpected observations that a marked drug could strongly inhibit the growth of Cryptosporidium in vitro, we plan to extend our discovery by screening all existing drugs for their potential ant-cryptosporidia activities in vitro and in vivo. Briefly, we will take advantage of established models and assays t achieve the following two aims: Aim 1. To identify potential anti-cryptosporidial compounds from known drugs in vitro using our well- developed and improved qRT-PCR assay. Aim 2. To determine anti-cryptosporidial efficacy of select drugs in vivo using acute and chronic mouse models of cryptosporidial infection. The majority of the compounds being screened are currently or previously marketed drugs. The proposed experiments examine the direct effects of drugs on the parasite growth in vitro and in vivo. Therefore, if satisfactory anti-cryptosporidial activitie in vitro and in vivo are observed among any of the FDS-approved drugs, these effective drugs can be rapidly moved to clinical trials and repurposed to become new drugs to treat cryptosporidial infection in humans, thus accelerating the drug discovery and development against Cryptosporidium. Furthermore, the project will nonetheless produce a large amount of data that profiles the activities of nearly all existing and abandoned drugs. The invaluable data can be used to analyze the structure-activity relationship (SAR) against Cryptosporidium to guide future drug development. PUBLIC HEALTH RELEVANCE: Project Narrative Cryptosporidium parvum is a Category B agent and an opportunistic pathogen in AIDS patients. Its infection in AIDS patients can be prolonged and deadly, for which no treatment is yet available. This is largely due to the technical difficulties in manipulating this parasite in laboratory and to the unusual metabolic features that are still poorly understood. This project takes advantage of an improved drug testing assay to unbiasedly, directly screen all existing drugs on their efficacies on the parasite growth in vitro. Top positive drugs will be further tested in vivo in a mouse model of chronic cryptosporidiosis. The majority of tested compounds are marked drugs for which toxicity and pharmacokinetics are known. Therefore, if any effective drugs are identified in this study, they can be quickly moved into clinic trials and/or "repurposed" as new drugs to treat cryptosporidiosis in humans and/or animals.

描述（由申请人提供）：小隐孢子虫是一种 AIDS-OI 病原体，也是 B 类病原体，可引起人类和动物严重的水样腹泻。这种寄生虫可以在免疫功能低下的个体中引起长期的、危及生命的感染，并导致艾滋病患者的很大程度的发病率和死亡率。此外，由于传染性卵囊对化学胁迫具有高度抵抗力，小小隐孢子虫是一种重要的水 和食源性病原体，是 NIH 生物防御计划中的 B 类病原体之一。目前，尽管在美国有一种药物（硝唑尼特）被批准用于免疫功能正常的患者，但 FDA 还没有批准用于治疗免疫功能低下患者的隐孢子虫病的药物。因此，迫切需要开发新的抗隐孢子虫药物，特别是针对艾滋病患者的新药。受近期“现有药物再利用”潜在新适应症发展的鼓舞，以及基于我们意外的观察结果，即一种标记药物可以在体外强烈抑制隐孢子虫的生长，我们计划通过筛选所有现有药物来扩展我们的发现因其潜在的体外和体内抗隐孢子虫活性。简而言之，我们将利用已建立的模型和测定来实现以下两个目标： 目标 1. 使用我们成熟且改进的 qRT-PCR 测定在体外从已知药物中鉴定潜在的抗隐孢子虫化合物。目标 2. 使用急性和慢性隐孢子虫感染小鼠模型确定选定药物的体内抗隐孢子虫功效。大多数正在筛选的化合物是目前或以前上市的药物。拟议的实验研究了药物对体外和体内寄生虫生长的直接影响。因此，如果任何FDS批准的药物在体外和体内观察到令人满意的抗隐孢子虫活性，这些有效的药物就可以迅速进入临床试验，并重新成为治疗人类隐孢子虫感染的新药，从而加速治疗人类隐孢子虫感染的新药。针对隐孢子虫的药物发现和开发。此外，该项目仍将产生大量数据，描述几乎所有现有和废弃药物的活动。这些宝贵的数据可用于分析隐孢子虫的构效关系 (SAR)，以指导未来的药物开发。 公共健康相关性：项目叙述隐孢子虫是 B 类病原体，也是艾滋病患者的机会性病原体。艾滋病患者的感染可能会持续很长时间并且致命，目前尚无治疗方法。这很大程度上是由于技术 在实验室中操纵这种寄生虫的困难以及不寻常的代谢特征 仍然知之甚少。该项目利用改进的药物测试方法，公正、直接地筛选所有现有药物对体外寄生虫生长的功效。 最阳性的药物将在慢性隐孢子虫病小鼠模型中进一步进行体内测试。大多数测试的化合物是已知毒性和药代动力学的标记药物。因此，如果在本研究中发现任何有效的药物，它们可以迅速进入临床试验和/或“重新利用”作为治疗人类和/或动物隐孢子虫病的新药。